Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.

Summary, in English

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121(∗)], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

• Författare: Gina M Peloso; Paul L Auer; Joshua C Bis; Arend Voorman; Alanna C Morrison; Nathan O Stitziel; Jennifer A Brody; Sumeet A Khetarpal; Jacy R Crosby; Myriam Fornage; Aaron Isaacs; Johanna Jakobsdottir; Mary F Feitosa; Gail Davies; Jennifer E Huffman; Ani Manichaikul; Brian Davis; Kurt Lohman; Aron Y Joon; Albert V Smith; Megan L Grove; Paolo Zanoni; Valeska Redon; Serkalem Demissie; Kim Lawson; Ulrike Peters; Christopher Carlson; Rebecca D Jackson; Kelli K Ryckman; Rachel H Mackey; Jennifer G Robinson; David S Siscovick; Pamela J Schreiner; Josyf C Mychaleckyj; James S Pankow; Albert Hofman; Andre G Uitterlinden; Tamara B Harris; Kent D Taylor; Jeanette M Stafford; Lindsay M Reynolds; Riccardo E Marioni; Abbas Dehghan; Oscar H Franco; Aniruddh P Patel; Yingchang Lu; George Hindy; Omri Gottesman; Erwin P Bottinger; Olle Melander; Marju Orho-Melander; Ruth J F Loos; Stefano Duga; Piera Angelica Merlini; Martin Farrall; Anuj Goel; Rosanna Asselta; Domenico Girelli; Nicola Martinelli; Svati H Shah; William E Kraus; Mingyao Li; Daniel J Rader; Muredach P Reilly; Ruth McPherson; Hugh Watkins; Diego Ardissino; Qunyuan Zhang; Judy Wang; Michael Y Tsai; Herman A Taylor; Adolfo Correa; Michael E Griswold; Leslie A Lange; John M Starr; Igor Rudan; Gudny Eiriksdottir; Lenore J Launer; Jose M Ordovas; Daniel Levy; Y-D Ida Chen; Alexander P Reiner; Caroline Hayward; Ozren Polasek; Ian J Deary; Ingrid B Borecki; Yongmei Liu; Vilmundur Gudnason; James G Wilson; Cornelia M van Duijn; Charles Kooperberg; Stephen S Rich; Bruce M Psaty; Jerome I Rotter; Christopher J O'Donnell; Kenneth Rice; Eric Boerwinkle; Sekar Kathiresan; L Adrienne Cupples
• Avdelning/ar: Diabetes - kardiovaskulär sjukdom; Kardiovaskulär forskning - hypertoni; EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health
• Publiceringsår: 2014
• Språk: Engelska
• Sidor: 223-232
• Publikation/Tidskrift/Serie: American Journal of Human Genetics
• Volym: 94
• Issue: 2
• Länkar: http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract; http://dx.doi.org/10.1016/j.ajhg.2014.01.009
• Dokumenttyp: Artikel i tidskrift
• Förlag: Cell Press
• Ämne: Medical Genetics
• Status: Published
• Forskningsgrupp: Diabetes - Cardiovascular Disease; Cardiovascular Research - Hypertension
• ISBN/ISSN/Övrigt: ISSN: 0002-9297